Polarized radial glial cells provide a template for the formation of cerebral cortex. Initially, they function as a source of new neurons and provide a permissive and instructive scaffold for neuronal migration. Subsequently, they contribute to the formation of glial cell lineages in the mature brain. Abnormalities in radial glial development, differentiation, and neuron- radial glial interactions lead to aberrant generation, placement and connectivity of neurons and glia in human brain, an underlying cause of many developmental brain disorders such as schizophrenia, and gross brain malformations that accompanies mental retardation and seizure disorders (reviewed in Marin and Rubinstein, 2003; Ayala et al., 2008; Ghashghaei et al., 2008). The aims of this proposal are to elucidate the molecular mechanisms regulating the polarity of radial glia and how radial glial polarity is translated into distinct radial glial functions. Our preliminary results show that Adenomatous Polyposis Coli (APC) serves an essential function in the development of polarized radial glial scaffold during brain development. APC signalling thus provides a unique avenue to examine the mechanisms that determine radial progenitor polarity and its contribution to the formation of cerebral cortex. Analysis of these processes, using APC signalling as a molecular model, assumes additional significance due the known effects of APC mutations in mental retardation, autism, and brain tumors (Attard et al., 2007; Barber et al., 1994; Finch et al., 2005; Gsmez Garcma and Knoers, 2008). Based on these findings, we hypothesize that APC is an essential regulator of distinct aspects of radial glial polarity and is critical for the construction of cerebral cortex. The proposed studies will test this hypothesis by examining the following three related questions: (1) What is the role of APC in the emergence and maintenance of radial glial polarity and the resultant formation of cerebral cortex?, 2) What are the signaling pathways mediating APC function in radial glial progenitors?, and (3) What is the function of APC in neuronal progeny of radial glia? Together, these studies will significantly advance our understanding of the role radial progenitors and their derivatives play in the emergence of cerebral cortex. Further, elucidating the role of APC signalling in cerebral cortical formation will help to delineate the biological basis of neurodevelopmental brain disorders and brain tumorogenesis. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Abnormalities in radial progenitor development, differentiation, and neuron- radial glial interactions lead to aberrant generation, placement and connectivity of neurons in human brain, an underlying cause of many developmental brain disorders such as schizophrenia, and gross brain malformations, such as lissencephaly, polymicrogyria, and heterotopias (reviewed in Marin and Rubinstein, 2003; Ayala et al., 2008; Ghashghaei et al., 2008). Characterization of signaling mechanisms controlling the polarity and differentiation of radial progenitors and their progeny, as outlined in this proposal, will significantly advance our understanding of the role radial progenitors and their derivatives play in the emergence and maintenance of the cerebral cortex. The use of APC signalling as a molecular model in these studies has significant additional human health relevance since germ-line mutations of the APC gene results in familial adenomatous polyposis (FAP) (Kinzler et al., 1991). The significance of APC in cerebral cortical development is evident in recent studies demonstrating that APC mutations in humans cause brain tumor polyposis (Attard et al., 2007). Mental retardation or autism is also evident in individuals with APC mutations (Barber et al., 1994; Finch et al., 2005). Therefore, elucidating the role of APC signalling in radial progenitors and their derivatives will help in deciphering the basic mechanisms guiding normal cerebral cortical development as well as in unveiling the pathogenesis of various developmental brain disorders.